Abuse of prescription opioids is on the rise, as are fatalities related to their abuse. These trends highlight the need for improved strategies for decreasing their abuse. One approach to reducing prescription opioid abuse is to alter the formulation of the medication by adding agents that cause untoward effects if drug intake exceeds the prescribed dose. Recent work in our laboratory has focused on the study of drugs as punishers in monkeys. We have found that the kappa opioid agonist, salvinorin A, when self-administered contingently with remifentanil (a mu opioid analogous to morphine) or cocaine, reduces the frequency of choice for these reinforcers. The prospect that kappa agonists can function as punishers is significant because they also produce analgesic effects that could enhance the clinical effectiveness of prescription opioids as combinatorial agents. However, kappa agonists cause significant aversive effects (e.g., dysphoria, psychotomimesis, sedation) that limit their clinical feasibility. Nalfurafine is an atypical kappa agonist that does not produce the dysphoric and psychotomimetic effects associated with other kappa agonists. It was recently approved for treatment of pruritis in Japan, which demonstrates its feasibility as a therapeutic in humans. Our preliminary data suggest that nalfurafine can reduce the reinforcing effects of oxycodone when the two are self- administered as mixtures in a manner that is consistent with a punishment mechanism. The research plan for the current proposal is to compare the effectiveness of nalfurafine as a punisher of oxycodone self- administration to other established drug punishers in monkeys. We will also determine if nalfurafine and other drug punishers modulate the anti-nociceptive effects of oxycodone. Lastly, we will use quantitative observational procedures to compare the side effect profiles of oxycodone-nalfurafine mixtures to the effects of oxycodone mixed with other drug punishers known to produce significant aversive effects. Our central hypothesis is that combinations of oxycodone and all drug punishers will result in self-administration patterns indicative of reduced abuse liability, but tht the anti-nociceptive effects of oxycodone will be augmented by nalfurafine while the side effects produced by the oxycodone-nalfurafine combinations will be moderate compared to the effects produced by combinations with other drug punishers. Together, these studies will address the clinically-significant problem of developing abuse-deterrent formulations (ADF) for prescription opioids that are effective at reducing abuse without compromising therapeutic effects or causing untoward effects sufficient to discourage appropriate clinical use. Successful completion of our proposed studies will make a significant impact on efforts to decrease prescription opioid abuse by establishing a basic science model for developing ADFs and by testing a promising compound that could pave the way for a new class of deterrents for reducing the abuse liability of prescription opioids.